Ganong's Review of Medical Physiology, 23rd Edition

CHAPTER 23Hormonal Control of Calcium & Phosphate Metabolism & the Physiology of Bone 373

proteases secreted by the cell break down collagen, forming a
shallow depression in the bone (Figure 23–12). The products
of digestion are then endocytosed and move across the osteo-
clast by transcytosis (see Chapter 2), with release into the
interstitial fluid. The collagen breakdown products have pyri-
dinoline structures, and pyridinolines can be measured in the
urine as an index of the rate of bone resorption.
Throughout life, bone is being constantly resorbed and new
bone is being formed. The calcium in bone turns over at a rate
of 100% per year in infants and 18% per year in adults. Bone

remodeling is mainly a local process carried out in small areas

by populations of cells called bone-remodeling units. First,

osteoclasts resorb bone, and then osteoblasts lay down new

bone in the same general area. This cycle takes about 100

days. Modeling drifts also occur in which the shapes of bones

change as bone is resorbed in one location and added in

another. Osteoclasts tunnel into cortical bone followed by

osteoblasts, whereas trabecular bone remodeling occurs on

the surface of the trabeculae. About 5% of the bone mass is

being remodeled by about 2 million bone-remodeling units in

the human skeleton at any one time. The renewal rate for

bone is about 4% per year for compact bone and 20% per year

for trabecular bone. The remodeling is related in part to the

stresses and strains imposed on the skeleton by gravity.

At the cell–cell level, there is some regulation of osteoclast

formation by osteoblasts via the RANKL–RANK and the

M-CSF–OPG mechanism; however, specific feedback mecha-

nisms of osteoclasts on osteoblasts are not well defined. In a

broader sense, the bone remodeling process is primarily under

endocrine control. Parathyroid hormone accelerates bone

resorption, and estrogens slow bone resorption by inhibiting

the production of bone-eroding cytokines. An interesting new

observation is that intracerebroventricular but not intravenous

leptin decreases bone formation. This finding is consistent

with the observations that obesity protects against bone loss

and that most obese humans are resistant to the effects of lep-

tin on appetite. Thus, there may be neuroendocrine regulation

of bone mass via leptin.

BONE DISEASE

The diseases produced by selective abnormalities of the cells

and processes discussed above illustrate the interplay of fac-

tors that maintain normal bone function.

In osteopetrosis, a rare and often severe disease, the osteo-

clasts are defective and are unable to resorb bone in their

usual fashion so the osteoblasts operate unopposed. The

result is a steady increase in bone density, neurologic defects

due to narrowing and distortion of foramina through which

nerves normally pass, and hematologic abnormalities due to

crowding out of the marrow cavities. Mice lacking the protein

encoded by the immediate-early gene c-fos develop osteo-

petrosis, and osteopetrosis also occurs in mice lacking the

PU.1 transcription factor. This suggests that all these factors

are involved in normal osteoclast development and function.

On the other hand, osteoporosis is caused by a relative

excess of osteoclastic function. Loss of bone matrix in this con-

dition (Figure 23–13) is marked, and the incidence of fractures

is increased. Fractures are particularly common in the distal

forearm (Colles fracture), vertebral body, and hip. All of these

areas have a high content of trabecular bone, and because tra-

becular bone is more active metabolically, it is lost more rap-

idly. Fractures of the vertebrae with compression cause

kyphosis, with the production of a typical “widow’s hump” that

is common in elderly women with osteoporosis. Fractures of

FIGURE 23–11 Structure of a typical long bone before (left)
and after (right) epiphysial closure. Note the rearrangement of cells
and growth of the bone as the epiphysial plate closes (see text for details).

FIGURE 23–12 Osteoclast resorbing bone. The edges of the
cell are tightly sealed to bone, permitting secretion of acid from the
ruffled apical membrane and consequent erosion of the bone under-
neath the cell. Note the multiple nuclei (n) and mitochondria (mi).
(Courtesy of R Baron.)

Epiphysis

Epiphysis

Diaphysis

Epiphysial

plate

Marrow

cavity

Compact

bone

Periosteum

Trabecular

bone

Bone-resorbing

compartment

Ruffled apical

membrane

Sealing

zone

Basolateralmembrane Integrins

Bone

matrix

n

n

n

mi

n